A method for treating psoriasis vulgaris in subjects with a history of treatment with biological agents by switching to an anti-IL-23p19 antibody.

Abstract

The present invention relates to a method for treating psoriasis vulgaris in a subject who has previously been treated with a biological agent for psoriasis vulgaris, comprising administering an effective amount of anti-IL-23p19 subunit antibody to the subject, and to the use of anti-IL-23p19 antibody in the treatment of psoriasis vulgaris in a subject who has previously been treated with a biological agent.

Description

Technical Field

[0001] The present invention relates to the use of an anti-IL-23p19 antibody in the treatment of a subject who has previously been treated for psoriasis with a biological agent, and to a method of treating said subject comprising administering to said subject an effective amount of an anti-IL-23p19 antibody, who has previously been treated for psoriasis with a biological agent.

Background Art

[0002] IL-23 is a heterodimeric cytokine of the IL-12 family members and consists of a p40 subunit and a p19 subunit. IL-23 activates a signaling pathway by binding to the IL-23 receptor (IL-23R) and the β1 subunit of the IL-12 receptor (IL-12Rβ1). IL-23 is structurally closely related to IL-12, but these two cytokines have different biological functions, and IL-12 and IL-23 promote Th1 cell response and Th17 cell response, respectively. IL-23 can independently differentiate naive CD4 + T cells into Th17 cells or can also differentiate with the help of other cytokines such as transforming growth factor (TGF)-β, IL-6, or IL-1β. Furthermore, it can promote the proliferation, differentiation, and maintenance of Th17 cells and innate immune cells. Stimulation of Th17 cells produces cytokines including IL-17, IL-22, tumor necrosis factor (TNF)-α, and granulocyte macrophage colony-stimulating factor (GM-CSF), which stimulate local tissue inflammation and other immune mediators through a wide range of immune-mediated inflammatory conditions. Chronic inflammation resulting from dysregulation of the IL-23 / Th17 / IL-17 response underlies the pathophysiology of many autoimmune diseases (including psoriasis, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, and asthma).

[0003] Psoriasis is a chronic, relapsing, inflammatory, systemic disease mediated by genetic, environmental, and immunological factors, and can develop at any age, regardless of gender. Typical clinical manifestations are scaly erythematous or plaque-like lesions that are localized or widespread, non-infectious, difficult to treat, and often lifelong. Psoriasis is classified into plaque psoriasis (including guttate psoriasis and vulgaris psoriasis), pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis.

[0004] Currently, the main systemic drug therapies for psoriasis in China include methotrexate (MTX), cyclosporine A, retinoids, and biological agents. In recent years, monoclonal antibody biological agents targeting cellular inflammatory factors have been increasingly used in severe psoriasis cases that are poorly responsive to conventional systemic drugs and severely impact quality of life. These biological agents include tumor necrosis factor (TNF)-α antagonists (etanercept, infliximab, and adalimumab), IL-12 / 23 antagonists (ustekinumab), and IL-17A antagonists (secukinumab). Recently developed humanized IgG1 monoclonal antibodies that bind to the IL-23p19 subunit, such as guselkumab (Johnson & Johnson), risankizumab (Abbrev), and tildrakizumab (Merck Sharp & Dohme), have shown remarkable efficacy in the treatment of psoriasis vulgaris and are used in many countries to treat moderate to severe cases of psoriasis vulgaris.

[0005] In the case of biological agents, some patients experience a loss of response after a certain period of treatment, meaning their symptoms recur. In such cases, the introduction of new treatment methods is necessary to effectively treat patients whose response has disappeared. Currently, the utilization rate of biological agents for psoriasis patients in China remains very low, and there is still a great demand for effective, safe, and low-cost domestically produced biological agents. Furthermore, for patients whose symptoms have been relieved by existing biological agents, switching to a simpler, easier-to-administer treatment that can maintain symptom relief may improve patient compliance and be more beneficial to the patient. [Overview of the project]

[0006] The object of the present invention is to satisfy an unmet need in the art by providing a method for switching the treatment of psoriasis vulgaris in subjects who have previously received biological agents for the treatment of psoriasis vulgaris to a recombinant anti-IL-23p19 antibody.

[0007] Purpose This invention provides the use of recombinant anti-IL-23p19 antibody in the treatment of psoriasis vulgaris in subjects who have previously received biological drug therapy for psoriasis vulgaris.

[0008] In a first embodiment, the present invention relates to the use of a recombinant anti-IL-23p19 antibody in the manufacture of a pharmaceutical product for treating psoriasis vulgaris in a subject.

[0009] In a second embodiment, the present invention relates to a recombinant anti-IL-23p19 antibody for use in the treatment of psoriasis vulgaris in a subject.

[0010] Further embodiments of the first and second aspects are as follows:

[0011] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein CDR1 of the heavy chain variable region comprises or consists of the amino acid sequence of SEQ ID NO: 1, CDR2 of the heavy chain variable region comprises or consists of the amino acid sequence of SEQ ID NO: 2, and CDR3 of the heavy chain variable region comprises or consists of the amino acid sequence of SEQ ID NO: 3; CDR1 of the light chain variable region comprises or consists of the amino acid sequence of SEQ ID NO: 4, CDR2 of the light chain variable region comprises or consists of the amino acid sequence of SEQ ID NO: 5, and CDR3 of the light chain variable region comprises or consists of the amino acid sequence of SEQ ID NO: 6.

[0012] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

[0013] In some embodiments, the recombinant anti-IL-23p19 antibody is an IgG1 antibody, and preferably comprises the heavy chain sequence of SEQ ID NO: 9, or a sequence having at least 90%, 95%, 98%, or 99% identity with SEQ ID NO: 9, and the light chain sequence of SEQ ID NO: 10, or a sequence having at least 90%, 95%, 98%, or 99% identity with SEQ ID NO: 10.

[0014] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain shown in SEQ ID NO: 9 and a light chain shown in SEQ ID NO: 10.

[0015] In some embodiments, subjects have previously received biological agents for the treatment of psoriasis vulgaris. In some embodiments, subjects are switched to the antibody of the present invention for the treatment of psoriasis vulgaris after having previously received biological agents for the treatment of psoriasis vulgaris.

[0016] In some embodiments, subjects may be subjects who have been regularly administered a biological agent according to a prescribed dose (for at least 4 months) prior to screening, or subjects who have not been regularly administered a biological agent according to a prescribed dose (for at least 4 months between the last dose and the first dose).

[0017] In some embodiments, subjects had not responded to or had a poor response to previous biological therapies. In some embodiments, subjects were being treated with biological agents but had lost or had an insufficient response. In some embodiments, subjects who had not responded to or had a poor response to previous biological therapies had an sPGA score of 2 or higher, or a cumulative body surface area involved in skin lesions of 3% or higher, or a PASI improvement of less than 75% after administration of the biological therapy.

[0018] In some embodiments, administration of the antibody of the present invention to subjects who have not responded or have responded poorly to previous biological therapies includes a treatment phase and a maintenance phase. In some embodiments, the frequency of administration of the antibody of the present invention in the treatment phase is once daily, twice weekly, once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or more. The administration cycle of the antibody of the present invention may be one week, two weeks, three weeks, one month, two months, three months, or more, and the intervals between each administration cycle may be the same or different. In one preferred embodiment, the treatment phase includes administering the anti-IL-23p19 antibody in weeks 0, 4, and 8. In some embodiments, the frequency of administration of the antibody of the present invention in the maintenance phase is once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or more. In some embodiments, the maintenance phase is continued for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In one preferred embodiment, maintenance phase administration is given once every 12 weeks until the final dose at week 32. In some embodiments, the anti-IL-23p19 antibody is administered to subjects who did not respond or responded poorly to previous biological therapy at weeks 0, 4, and 8, respectively, and thereafter every 12 weeks. In some embodiments, the anti-IL-23p19 antibody is administered to subjects who lost or responded poorly to previous biological therapy at weeks 0, 4, and 8, respectively, and thereafter every 12 weeks until the final dose at week 32.

[0019] In some embodiments, the dosage for each administration is selected from 100 mg to 1000 mg, preferably 150 mg to 800 mg, for example, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In some embodiments, the dose of each anti-IL-23P19 antibody is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In a preferred embodiment, the dose of each antibody is 200 mg.

[0020] In some embodiments, subjects who have not responded or have responded poorly to previous biological therapies are administered 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively, followed by 200 mg of anti-IL-23p19 antibody once every 12 weeks. In some embodiments, subjects who have not responded or have responded poorly to previous biological therapies are administered 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively, followed by 200 mg of anti-IL-23p19 antibody every 12 weeks until the final week 32.

[0021] In some embodiments, the subject is a previous responder to the biological agent. In some embodiments, the subject has been treated with the biological agent and is still responding. In some embodiments, the subject has an sPGA score of 0 or 1, a cumulative body surface area of ​​skin lesions of less than 3%, or a PASI improvement of 75% or more after use of the biological agent.

[0022] In some embodiments, for subjects who have previously responded to biological treatment, the administration frequency of the antibody of the present invention is once daily, twice weekly, once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or more. The administration cycle of the antibody of the present invention may be one week, two weeks, three weeks, one month, two months, three months, or more, and the intervals between each administration cycle may be the same or different. In one preferred embodiment, the anti-IL-23p19 antibody is administered in week 0. In some embodiments, after the week 0 administration, administration intervals of once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or more are maintained. In some embodiments, maintenance administration is continued for at least 24, 28, 32, 36, 40, 44, 48 weeks, or more. In one preferred embodiment, maintenance administration is then administered once every twelve weeks. In one preferred embodiment, in subjects who have responded to prior biological therapy, the anti-IL-23p19 antibody is administered at week 0 and thereafter every 12 weeks. In one embodiment, in subjects who have responded to prior biological therapy, the anti-IL-23p19 antibody is administered at week 0 and thereafter every 12 weeks until the final week 36.

[0023] In some embodiments, the dosage for each administration is selected from 100 mg to 1000 mg, preferably 150 mg to 800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In some embodiments, the anti-IL-23p19 antibody is administered at a dosage of 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In a preferred embodiment, the dosage for each administration is 200 mg.

[0024] In some embodiments, for subjects who responded to previous biological therapies, 200 mg of the anti-IL-23p19 antibody is administered at week 0, and then 200 mg of the anti-IL-23p19 antibody is administered every 12 weeks thereafter. In some embodiments, for subjects who responded to previous biological therapies, 200 mg of the anti-IL-23p19 antibody is administered at week 0, and then 200 mg of the anti-IL-23p19 antibody is administered every 12 weeks until week 三十六 (36) of the final administration.

[0025] In some embodiments, the biological agent includes a tumor necrosis factor α (TNF-α) inhibitor / antagonist and / or an IL-17A inhibitor / antagonist.

[0026] In some embodiments, the TNF-α inhibitor / antagonist includes etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), and certolizumab (Cimzia).

[0027] It should be noted that in the translation of the number "三十六 (36)" in the fourth paragraph, it is not clear what the specific intention is. It may be a typo or an unclear expression in the original text. If it is a specific number in Chinese that needs to be accurately translated according to the context, it should be further clarified. Here, it is tentatively translated as "三十六 (36)".In some embodiments, the IL-17A inhibitors / antagonists include secukinumab (Cosentyx) and ixekizumab (Taltz).

[0028] In some embodiments, the anti-IL-23p19 antibody of the present invention is formulated in the form of a liquid pharmaceutical composition for administration. Useful carriers and solvents include water, Ringer's solution, phosphate-buffered saline, isotonic sodium chloride solution, and the like. Furthermore, sterilized fixed oils can also be appropriately used as solvents or suspension media. Any mixed non-volatile mineral oil or non-mineral oil containing synthetic monoglycerides or diglycerides can be used for this purpose. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injections.

[0029] In some embodiments, the pharmaceutical composition containing the anti-IL-23p19 antibody of the present invention is an injection solution or a dry powder formulation. For example, the composition is a lyophilized powder, which can be reconstituted into an injection solution in a pharmaceutically acceptable liquid carrier. Pharmaceutically acceptable liquid carriers include, for example, sterile water, Ringer's solution, phosphate-buffered saline, isotonic sodium chloride solution, and the like.

[0030] In some embodiments, the anti-IL-23p19 antibody of the present invention is administered topically.

[0031] In some embodiments, the anti-IL-23p19 antibody of the present invention is administered by subcutaneous injection.

[0032] In some embodiments, the subject does not experience severe adverse events after administration.

[0033] In some embodiments, after administration, the incidence of adverse events in the subject is comparable to the incidence in subjects administered placebo.

[0034] In some embodiments, the subject is human.

[0035] In some embodiments, administration of the anti-IL-23p19 antibody of the present invention to subjects can improve psoriatic skin lesions and quality of life in subjects who have not responded or have responded poorly to previous biological treatments. In some embodiments, administration of the anti-IL-23p19 antibody of the present invention to subjects allows subjects who have responded to previous biological treatments to maintain or improve their response to treatment (e.g., improve skin lesions), maintain or improve their current quality of life.

[0036] In one preferred embodiment, the anti-IL-23p19 antibody of the present invention can achieve one or more of the following effects in a subject:

[0037] The maximum dosing interval for previous IL-17 and TNF class drugs was once every four weeks, which involved relatively frequent administration and can be burdensome for patients. In contrast, administering the anti-IL-23p19 antibody of the present invention according to the dosing schedule described herein not only simplifies and simplifies the administration procedure due to the reduced frequency of administration, but also improves patient medication compliance and quality of life.

[0038] According to the trial data, among subjects who showed a baseline clinical response, 85.3% of those who switched to anti-IL-23p19 antibody therapy maintained a clinical response at week 16 (cumulative body surface area of ​​skin lesions less than 3% and a physician-administered static overall assessment (sPGA) score of 0 or 1), and the response rate remained stable at approximately 85% from week 16 to the end of the observation period at week 36. In contrast, among subjects who did not show a clinical response at baseline, some who switched to the aforementioned antibody therapy began to show a clinical response, and the response rate gradually increased to 52.1% by week 16 and remained at a similar level thereafter.

[0039] Treatment method In a third embodiment, the present invention relates to a method for treating psoriasis vulgaris in a subject, comprising administering the subject an effective amount of recombinant anti-IL-23p19 antibody.

[0040] In a fourth embodiment, the present invention provides a method for treating psoriasis vulgaris in a subject who has previously been administered a biological agent, wherein the subject is switched to administration of recombinant anti-IL-23p19 antibody.

[0041] Further embodiments in the third and fourth embodiments are as follows:

[0042] In some embodiments, the anti-IL-23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region includes or consists of SEQ ID NO: 1, the amino acid sequence of CDR2 of the heavy chain variable region includes or consists of SEQ ID NO: 2, and the amino acid sequence of CDR3 of the heavy chain variable region includes or consists of SEQ ID NO: 3; the amino acid sequence of CDR1 of the light chain variable region of the antibody includes or consists of SEQ ID NO: 4, the amino acid sequence of CDR2 of the light chain variable region includes or consists of SEQ ID NO: 5, and the amino acid sequence of CDR3 of the light chain variable region includes or consists of SEQ ID NO: 6.

[0043] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

[0044] In some embodiments, the recombinant anti-IL-23p19 antibody is an IgG1 antibody, preferably comprising the heavy chain sequence of SEQ ID NO: 9, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain sequence of SEQ ID NO: 10, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

[0045] In some embodiments, the recombinant anti-IL-23p19 antibody comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0046] In some embodiments, subjects have previously received biological agents for the treatment of psoriasis vulgaris. In some embodiments, subjects are switched to the antibody of the present invention for the treatment of psoriasis vulgaris after having previously received biological agents for the treatment of psoriasis vulgaris.

[0047] In some embodiments, prior to screening, subjects may be those who have been regularly administered the biological agent according to a prescribed dose (for at least 4 months), or they may not be those who have been regularly administered the biological agent according to a prescribed dose (for at least 4 months between the last dose and the first dose).

[0048] In some embodiments, the method involves administering an anti-IL-23p19 antibody to a subject who has previously been treated with a biological agent for psoriasis vulgaris.

[0049] In some embodiments, subjects have not responded or have responded poorly to previous biological therapies. In some embodiments, subjects are being treated with biological agents but have not responded or have responded poorly. In some embodiments, subjects who have not responded or responded poorly to previous biological agents have an sPGA score of 2 or higher, a cumulative body surface area affected by skin lesions of 3% or higher, or a PASI improvement of less than 75% after administration of the biological agent.

[0050] In some embodiments, for subjects who have not responded or have responded poorly to previous biological therapies, the method of the present invention involves administering the antibody of the present invention in two phases (i.e., a treatment phase and a maintenance phase). In some embodiments, during the treatment phase, the administration frequency of the antibody of the present invention is once daily, twice weekly, once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or more. The administration cycle of the antibody of the present invention may be one week, two weeks, three weeks, one month, two months, three months, or more, and the intervals between each administration cycle may be the same or different. In one preferred embodiment, the treatment phase includes administering the anti-IL-23p19 antibody at week 0, week 4, and week 8. In some embodiments, during the maintenance phase, the administration frequency of the antibody of the present invention is once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or more. In some embodiments, the maintenance phase lasts for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In one preferred embodiment, the maintenance phase is administered once every 12 weeks until the final dose at week 32. In some embodiments, the anti-IL-23p19 antibody is administered to subjects who have not responded or responded poorly to previous biological therapies at weeks 0, 4, and 8, respectively, and thereafter every 12 weeks. In some embodiments, the anti-IL-23p19 antibody is administered to subjects who have not responded or responded poorly to previous biological therapies at weeks 0, 4, and 8, respectively, and thereafter every 12 weeks until the final dose at week 32.

[0051] In some embodiments, the dosage for each administration is 100 mg to 1000 mg, preferably 150 mg to 800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In some embodiments, the dose of each administration is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg of anti-IL-23p19 antibody. In a preferred embodiment, the dose of each administration is 200 mg.

[0052] In some embodiments, subjects who have not responded or have responded poorly to previous biological therapies are administered 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively, followed by a 200 mg dose of anti-IL-23p19 antibody every 12 weeks thereafter. In some embodiments, subjects who have not responded or have responded poorly to previous biological therapies are administered 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively, followed by a 200 mg dose of anti-IL-23p19 antibody every 12 weeks until the final dose at week 32.

[0053] In some embodiments, the subject is a responder to prior biological therapy. In some embodiments, the subject is being treated with a biological agent and is still responding. In some embodiments, the subject has an sPGA score of 0 or 1, a cumulative body surface area of ​​skin lesions of less than 3%, or a PASI improvement of 75% or more after use of the biological agent.

[0054] In some embodiments, for subjects who have previously responded to biological treatment, the administration frequency of the antibody of the present invention is once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or once every twelve weeks, once every sixteen weeks, once every twenty weeks, or more. The administration cycle of the antibody of the present invention may be one week, two weeks, three weeks, one month, two months, three months, or more, and the intervals between each administration cycle may be the same or different. In one preferred embodiment, the anti-IL-23p19 antibody is administered in week 0. In some embodiments, after the week 0 administration, administration is maintained at intervals of once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or more. In some embodiments, maintenance administration continues for at least 24, 28, 32, 36, 40, 44, 48 weeks, or more. In a preferred embodiment, maintenance doses are administered once every 12 weeks for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In a preferred embodiment, the anti-IL-23p19 antibody is administered to subjects who have responded to prior biological therapy at week 0, and thereafter every 12 weeks for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In one embodiment, the anti-IL-23p19 antibody is administered to subjects who have responded to prior biological therapy at week 0, and thereafter every 12 weeks until the final dose at week 36.

[0055] In some embodiments, the dosage for each administration is selected from 100 mg to 1000 mg, preferably 150 mg to 800 mg, for example, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In some embodiments, the dose of each administration is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg of anti-IL-23p19 antibody. In a preferred embodiment, the dose per administration is 200 mg.

[0056] In some embodiments, subjects who have responded to prior biological therapy are administered 200 mg of anti-IL-23p19 antibody at week 0, and then 200 mg of anti-IL-23p19 antibody every 12 weeks thereafter. In some embodiments, subjects who have responded to prior biological therapy are administered 200 mg of anti-IL-23p19 antibody at week 0, and then 200 mg of anti-IL-23p19 antibody every 12 weeks until the final dose at week 36.

[0057] In some embodiments, the biological agent includes tumor necrosis factor α inhibitors / antagonists and / or IL-17A inhibitors / antagonists.

[0058] In some embodiments, TNF-α inhibitors / antagonists include etanercept, infliximab, adalimumab, golimumab, and trastuzumab.

[0059] In some embodiments, IL-17A inhibitors / antagonists include secukinumab and ixekizumab.

[0060] In some embodiments, the anti-IL-23p19 antibody is recombinantly expressed in HEK293 cells or CHO cells.

[0061] In some embodiments, the anti-IL-23p19 antibody of the present invention is formulated in the form of a liquid pharmaceutical composition for administration. Useful carriers and solvents include water, Ringer's solution, phosphate-buffered saline, isotonic sodium chloride solution, and the like. Furthermore, sterile fixative oils may be used as solvents or suspension media as appropriate. Any mixed non-volatile mineral oil or non-mineral oil containing synthetic monoglycerides or diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid can also be used in the preparation of injectable formulations.

[0062] In some embodiments, the pharmaceutical composition comprising the anti-IL-23p19 antibody of the present invention is an injectable solution or a dried powder formulation. For example, the composition is a lyophilized powder which can be reconstituted into an injectable solution in a pharmaceutically acceptable liquid carrier. Examples of pharmaceutically acceptable liquid carriers include sterile water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution.

[0063] In some embodiments, the anti-IL-23p19 antibody or pharmaceutical composition of the present invention is administered topically.

[0064] In some embodiments, the anti-IL-23p19 antibody or pharmaceutical composition of the present invention is administered by subcutaneous injection.

[0065] In some embodiments of the above method, subjects do not experience serious adverse events after administration.

[0066] In some embodiments of the above method, the incidence of adverse events in subjects after administration is similar to that in subjects who received a placebo.

[0067] In some embodiments of the above method, the subject is a human.

[0068] The present invention's method for treating psoriasis vulgaris in a subject who has previously been treated with a biological agent, comprising switching the subject to a recombinant anti-interleukin-23p19 subunit antibody, can treat subjects with psoriasis vulgaris who are being treated with a biological agent but are unresponsive or poorly responding to the biological therapy, resulting in improvement of the psoriatic lesions and an improvement in the quality of life of such subjects. Furthermore, the method can also treat subjects with psoriasis vulgaris who are being administered a biological agent and are still responding to it, resulting in such subjects being able to sustain or improve their therapeutic response (e.g., improvement of psoriatic skin lesions), and maintain or improve their current quality of life.

[0069] Compared to similar methods, the method of the present invention can include psoriasis subjects who have lost responsiveness to biological agents and those who have responded to biological agents. Furthermore, actual clinical administration of biological agents does not always fully follow the instructions for use. The method of the present invention shows a certain therapeutic effect not only in patients who have been switched to the anti-IL-23p19 antibody of the present invention in accordance with the instructions for use, but also in patients who have been switched to this antibody without following the instructions for use, and therefore covers a broader patient population.

[0070] In one preferred embodiment, the anti-IL-23p19 antibody of the present invention can achieve one or more of the following effects in a subject:

[0071] The maximum dosing interval for conventional IL-17 and TNF class drugs is once every four weeks, which involves relatively frequent administration and therefore tends to be inconvenient for patients. In contrast, administering the anti-IL-23p19 antibody of the present invention according to the dosing schedule described herein not only simplifies the administration procedure and improves convenience by reducing the frequency of administration, but also improves patient compliance and quality of life.

[0072] According to the trial data, of the subjects who showed a clinical response at baseline after switching to anti-IL-23p19 antibody therapy, 85.3% maintained a clinical response at week 16 (cumulative body surface area affected by skin lesions was less than 3%, and the physician's static overall assessment (sPGA) score was 0 or 1), and the response rate remained stable at approximately 85% from week 16 to the final week 36 of the observation period. Among the subjects who did not show a clinical response at baseline, some who were switched to the aforementioned antibody therapy began to show a clinical response, and the response rate gradually increased to 52.1% at week 16 and remained at a similar level thereafter.

[0073] It should be understood that technical solutions obtained from any combination of the technical features described in the first and second embodiments and the technical features described in the third and fourth embodiments are also included in the present invention.

[0074] Single drug administration unit or drug kit In a fifth embodiment, the present invention relates to a single drug administration unit comprising the anti-IL-23p19 antibody of the present invention.

[0075] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region and a light chain variable region, where the amino acid sequence of CDR1 of the heavy chain variable region comprises or consists of SEQ ID NO: 1, the amino acid sequence of CDR2 of the heavy chain variable region comprises or consists of SEQ ID NO: 2, and the amino acid sequence of CDR3 of the heavy chain variable region comprises or consists of SEQ ID NO: 3; the amino acid sequence of CDR1 of the light chain variable region comprises or consists of SEQ ID NO: 4, the amino acid sequence of CDR2 of the light chain variable region comprises or consists of SEQ ID NO: 5, and the amino acid sequence of CDR3 of the light chain variable region comprises or consists of SEQ ID NO: 6.

[0076] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

[0077] In some embodiments, the recombinant anti-IL-23p19 antibody is an IgG1 antibody, preferably comprising the heavy chain sequence of SEQ ID NO: 9 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain sequence of SEQ ID NO: 10 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

[0078] In some embodiments, the recombinant anti-IL-23p19 antibody comprises the heavy chain described in SEQ ID NO: 9 and the light chain described in SEQ ID NO: 10.

[0079] In some embodiments, a single drug dose unit comprises the following dosages of anti-IL-23p19 antibody: a fixed dose of 10 to 100 mg, preferably 50 to 800 mg, more preferably 50 to 500 mg, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg. 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, or 1000mg.

[0080] In some embodiments, a single drug dose unit is a single drug dose unit filled in a pre-filled auto-injector pen.

[0081] In a sixth embodiment, the present invention relates to a pharmaceutical kit comprising the anti-IL-23p19 antibody of the present invention as described in any one of the above embodiments of a single pharmaceutical administration unit.

[0082] In a seventh embodiment, the present invention relates to the use of the above-mentioned single drug administration unit or drug kit in the manufacture of a drug for the treatment of psoriasis vulgaris.

[0083] In some embodiments, the above-described single drug dose unit or drug kit is provided for use in the treatment of psoriasis vulgaris.

[0084] It should be understood that a technical solution obtained from any combination of any of the technical features described in the fifth to seventh aspects above and any of the technical features of the technical solutions described in the first to fourth aspects is also included in the present invention.

[0085] Other embodiments of the present invention will become apparent from the following detailed description and will be described with reference thereto. [Modes for carrying out the invention]

[0086] Detailed description of the invention Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions described herein, and such methods and conditions may be modified. Furthermore, the terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit them.

[0087] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. For the purposes of the present invention, the following terms are defined below.

[0088] When used in conjunction with a number, the term "approximately" is intended to encompass a range of numbers from a lower limit of 5% less than the specified number to an upper limit of 5% more than the specified number.

[0089] When the term "and / or" is used to link two or more options, it should be understood to refer to one of the options or two or more of the options.

[0090] In this specification, the terms “comprise” or “include” mean that the described element, integer, or process is included, but not that other elements, integers, or processes are excluded. As used herein, the terms “comprise” or “include” also encompass situations where the whole consists of the described element, integer, or process, unless otherwise specified. For example, when referring to an antibody variable region that “includes” a particular sequence, it is intended to also include the antibody variable region consisting of that particular sequence.

[0091] The IL-23 p19 subunit (hereinafter also referred to herein as "IL-23p19" or "p19 subunit") is a 189-amino acid polypeptide containing a 21-amino acid leader sequence (Oppmann et al., Immunity 13:715 (2000), SEQ ID NO: 181) and four packed alpha helices named A, B, C, and D, having an up-up-down-down topology. The four helices are connected by three polypeptide loops. The AB and CD loops are relatively long as they connect parallel helices. The short BC loop connects the antiparallel B and C helices. The IL-23 p19 subunit is a member of the IL-6 family of helical cytokines. This cytokine family binds to its syncytial receptors via three conserved epitopes (sites I, II, and III; bravo and Heath (2000) EMBO J.19:2399-2411). The p19 subunit interacts with the three cytokine receptor subunits to form a potent signaling complex. When expressed intracellularly, the p19 subunit first complexes with the p40 subunit, which is shared by the p19 subunit and IL-12. The p19p40 complex is secreted from the cell as a heterodimeric protein called IL-23. In one embodiment, the IL-23p19 of the present invention is derived from humans (NCBI:AAG37232) or cynomolgus monkeys (NCBI:AEY84629).

[0092] As used herein, the terms “anti-IL-23p19 antibody,” “anti-IL-23p19,” “recombinant anti-IL-23p19 antibody,” “IL-23p19 antibody,” or “antibody that binds to IL-23p19” refer to an antibody that can bind with sufficient affinity to (human or cynomolgus monkey) IL-23p19 subunits or fragments thereof, and such antibodies can therefore be used as diagnostic and / or therapeutic agents targeting (human or cynomolgus monkey) IL-23p19.

[0093] As used herein, the term “antibody” is used in its broadest sense to refer to proteins containing antigen-binding sites, and also encompasses natural and artificial antibodies of various structures (including, but not limited to, undenatured antibodies and antigen-binding fragments of antibodies).

[0094] The terms "whole antibody," "full-length antibody," "complete antibody," and "undenatured antibody" are used interchangeably to refer to glycoproteins containing at least two heavy chains (H chains) and two light chains (L chains) linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (hereinafter abbreviated as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (hereinafter abbreviated as VL) and a light chain constant region. The light chain constant region consists of one domain (CL). The VH and VL regions are further subdivided into highly variable regions called complementarity-determining regions (CDRs), which incorporate more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxyl terminus. The constant region does not directly participate in antibody-antigen binding, but it exerts various effector functions.

[0095] A "complementarity-determining region," "CDR region," or "CDR" is a region within the antibody variable domain that is highly sequence-variable, forms a structurally distinct loop ("hypervariable loop"), and / or contains an antigen contact residue ("antigen contact site"). CDRs are primarily responsible for binding to the antigen epitope. Heavy chain and light chain CDRs are generally called CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus. CDRs located in the heavy chain variable domain of the antibody are called HCDR1, HCDR2, and HCDR3, and CDRs located in the light chain variable domain of the antibody are called LCDR1, LCDR2, and LCDR3.

[0096] In specific amino acid sequences within the light chain variable region or heavy chain variable region, the precise amino acid sequence boundaries of each CDR can be determined using one or a combination of many well-known antibody CDR assignment systems. These systems include, for example, Chothia (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), which is based on the three-dimensional structure of antibodies and the topology of the CDR loop; Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, US Department of Health and Human Services, National Institutes of Health (1987)), which is based on the mutability of antibody sequences; AbM (University of Bath); Contact (University College London); the International ImMunoGeneTics database (IMGT) (World Wide Web imgt.cines.fr / ); and the North CDR definition based on affinity propagation clustering using numerous crystal structures.

[0097] Unless otherwise specified, the residue positions of the antibody variable region (including heavy chain variable region residues and light chain variable region residues) are numbered according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0098] In one embodiment, the CDR boundary of the antibody of the present invention is determined by the AbM rule.

[0099] An "antibody fragment" refers to a molecule other than the undenatured antibody that binds to the antigen to which the undenatured antibody binds, and which includes a portion of the undenatured antibody. Examples of antibody fragments, but are not limited to, include Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies; linear antibodies, single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent antibodies or bispecific antibodies or their fragments; camelid antibodies; and bispecific or multispecific antibodies formed from antibody fragments.

[0100] "To treat" means to slow, interrupt, stop, alleviate, halt, reduce, or restore the progression or severity of an existing symptom, disorder, condition, or disease.

[0101] The term "effective dose" refers to the amount or dosage of the formulation or antibody of the present invention that, after being administered to a patient once or multiple times, produces the desired effect in the patient. The effective dose can be easily determined by a physician skilled in the art by considering a variety of factors, including the species, size, age, and general health of the patient (such as mammals); the specific disease involved; the degree or severity of the disease; the response in the individual patient; the specific antibody administered; the method of administration; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; and the use of combination therapy.

[0102] The "therapeutic dose" refers to the amount that effectively achieves the desired therapeutic outcome in the required dosage and for the required duration. The therapeutic dose of the formulation, antibody, antibody fragment, or complex or composition thereof of the present invention may vary depending on various factors such as the individual's medical condition, age, sex, and weight, as well as the individual's ability to induce the desired response with the antibody or antibody moiety. The therapeutic dose is also the amount in which the toxicity or adverse effects of the formulation, antibody, antibody fragment, or complex or composition thereof are less than the therapeutically beneficial effects of the therapeutic dose.

[0103] "Formulation" or "pharmaceutical composition" refers to a composition comprising at least one active ingredient and at least one inactive ingredient suitable for administration to animals, preferably mammals including humans. "Liquid formulation" or "liquid composition" refers to a formulation in liquid form. The liquid composition of the present invention comprises (i) the antibody of the present invention, (ii) a buffer, and (iii) a vehicle. The composition of the formulation of the present invention may be as shown in the embodiments relating to the liquid pharmaceutical composition described above. The liquid formulations disclosed herein are preferably injectable.

[0104] A "medically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Medically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0105] In this specification, "buffering agent" refers to a pH buffering agent. For example, buffering agents are selected from histidine, glutamate, phosphate, acetate, citrate, and tris(hydroxymethyl)aminomethane.

[0106] As used herein, the term "vehicle" refers to a liquid used to dissolve or suspend active and inactive ingredients to form a liquid formulation. Vehicles that can be used in the present invention include, but are not limited to, water for injection, and organic solvents for injection (including, but not limited to, oil for injection, ethanol, propylene glycol, etc., or combinations thereof).

[0107] "sPGA" stands for Static Physician's Global Assessment, and it is a record of a physician's assessment of a subject's psoriasis condition (including manifestations such as induration, scaling, and erythema). It is used to assess a subject's psoriatic skin lesions at a specific point in time. All skin lesions were graded according to the following ranges of induration, erythema, and scaling. The sPGA score is calculated by dividing the sum of the three scores by three, as shown below.

[0108] Induration (I) [Average of all skin lesions; measured using the NPF National Psoriasis Foundation Reference card] 0 = No evidence of plaque elevation 1 = Microplaque elevation, 0.25 mm 2 = Mild plaque elevation, 0.5 mm 3 = Moderate plaque elevation, 0.75 mm 4 = Significant plaque elevation, 1 mm 5 = Severe plaque elevation, ≥1.25mm

[0109] Erythema (E) (average of all skin lesions) 0 = No evidence of erythema, but hyperpigmentation may be present. 1 = Faint erythema 2 = Slightly red 3 = Moderate red 4 = Bright red 5 = Dark red to deep red

[0110] Scaling (S) (average of all skin lesions) 0 = No evidence of scaling. 1 = Mild scaling; scaling is sometimes observed, but accounts for less than 5% of all skin lesions. 2 = Mild; fine scales are predominant. 3 = Moderate: Coarse scales are predominant. 4 = Prominent: Thick, intractable scales are predominant. 5 = Severe: Predominance of very thick, intractable scales.

[0111] sPGA overall average score = I + E + S / 3 sPGA (Physician's Static Overall Assessment) is evaluated based on the total average score: 0 = Good condition except for some remaining discoloration. 1 = Minor; most skin lesions are rated 1 point individually. 2 = Mild; most skin lesions are scored 2 points individually. 3 = Moderate, most skin lesions are scored 3 points individually. 4 = Significant, most skin lesions are individually rated 4 points. 5 = Severe; most skin lesions are scored 5 points individually.

[0112] Note: Fractions are rounded to the nearest integer. If the total score is less than 1.50, score = 1; if the total score is ≥ 1.50, score = 2.

[0113] sPGA-G performs a local assessment of perineal psoriasis using the sPGA evaluation criteria and evaluates it on a score from 0 to 5.

[0114] PASI stands for Psoriasis Area and Severity Index, a systematic tool for evaluating and grading the severity of psoriatic skin lesions and their response to treatment. The PASI score ranges from 0 to 72. The percentage of body surface area affected is linearly correlated with the severity of erythema, induration, and scaling in four body parts. This evaluation item is based on the percentage reduction from baseline and is usually summarized as a binomial distribution based on the achievement of an X% reduction (or PSAIx), where X is 50, 75, 90, and 100. To calculate PASI, the areas of four major body parts, namely the head (h), torso (t), upper limbs (u), and lower limbs (l), are evaluated, accounting for 10%, 30%, 20%, and 40% of the total body surface area, respectively.

[0115] The areas affected by psoriasis in these four sites are represented numerically: 0 Orders unaffected 1 = less than 10% 2 = 10% to less than 30% 3 = 30% to less than 50% 4 = 50% to less than 70% 5 = 70% to less than 90% 6 = 90%~100%

[0116] The severity of skin lesions, indicated by erythema (E), induration (I), and scaling (S), is assessed using a scale from 0 to 4, where 0 is no skin lesion, 1 is mild, 2 is moderate, 3 is severe, and 4 is very severe; the scores for the four sites are listed separately.

[0117] To assist in the evaluation of the area, please keep the following points in mind: a. The neck belongs to the head. b. The armpits and groin are part of the torso. c. The buttocks belong to the lower limbs.

[0118] PASI=0.1 * (Eh+Ih+Sh)Ah+0.3 * (Et+It+St)At+0.2 * (Eu+Iu+Su)Au+0.4 * (E1+Il+S1)A1.

[0119] "DLQI" stands for Dermatology Life Quality Index, a dermatology-related quality of life assessment tool used to evaluate the impact of disease on a subject's quality of life (AY Finlay and GK Khan). Using a 10-question questionnaire, six different aspects of quality of life are assessed: symptoms and emotions, daily activities, leisure activities, work or school standards, relationships, and treatment. The DLQI is administered over a one-week recall period. Response categories are: no problem (0), no problem at all (0), almost no problem (1), serious (2), and very serious (3). For question 7, if the answer is "yes" or "no," "yes" is worth 3 points.

[0120] The DLQI is voluntarily completed by the subject during each visit marked on the flowchart.

[0121] DLQI was analyzed from the following six aspects. [Table 1] [Table 2]

[0122] For item 7, select "Yes," and if the score reaches the maximum of 3 points, select "No," then select a score from the table according to your choice.

[0123] The total DLQI score is calculated by summing the scores for each question, and the result is displayed on a scale of 0 to 30. A higher score indicates a lower quality of life. 0-1 point: No impact on the subject's life. 2-5 points: Small impact, 6-10 points: The impact is moderate. 11-20 points: The impact is very significant. 21-30 points: Significantly impacts the subject's life.

[0124] If an answer to a question regarding a particular aspect was missing, that aspect was considered missing. If two or more questions were unanswered, the total DLQI score was considered missing. A change of 5 points from baseline was considered a clinically significant difference.

[0125] As used herein, the term “single-dose drug unit” refers to a single-dose drug formulation containing the antibody of the present invention administered to a subject at the time of administration, such as a vial, ampoule, filled syringe, or pre-filled syringe for injection, which may include a drug solution or lyophilized powder.

[0126] Treatment method The present invention provides a method for switching subjects who have previously received biological agents for the treatment of psoriasis vulgaris to an anti-IL-23p19 antibody for the treatment of psoriasis vulgaris.

[0127] In some specific embodiments of the present invention, the amino acid sequence of the heavy chain CDR1 of the anti-IL-23p19 antibody comprises SEQ ID NO: 1, the amino acid sequence of the heavy chain CDR2 comprises SEQ ID NO: 2, and the amino acid sequence of the heavy chain CDR3 comprises SEQ ID NO: 3; the amino acid sequence of the light chain CDR1 of the antibody comprises SEQ ID NO: 4, the amino acid sequence of the light chain CDR2 comprises SEQ ID NO: 5, and the amino acid sequence of the light chain CDR3 comprises SEQ ID NO: 6.

[0128] In one specific embodiment of the present invention, the method comprises an anti-IL-23p19 antibody that specifically binds to IL-23p19 and includes the following six CDRs: - Represented by the heavy chain VHCDR1, GYTFTSYLMH (SEQ ID NO: 1); - Represented by heavy-chain VHCDR2, YINPYNEGTN (SEQ ID NO: 2): - Represented by heavy-chain VHCDR3, NWDLPY (SEQ ID NO: 3): - Light chain VLCDR1, indicated by RASQSISDYLH (SEQ ID NO: 4): - Light chain VLCDR2, indicated by YASQSMS (SEQ ID NO: 5): - Represented by the light chain VLCDR3, QQGHSFPFT (SEQ ID NO: 6).

[0129] In one specific embodiment, the anti-IL-23p19 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8, or a sequence having at least 90%, 95%, 98%, or 99% identity thereto:

[0130] Array (sequence number 7): QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYLMHWVRQAPGQGLEWMGYINPYNEGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARNWDLPYWGQGTLVTVSS

[0131] Array (array number: 8) DIQMTQSPSSLSASVGDRVTITCRASQSISDYLHWYQQKPGKAPKLLIKYASQSMSGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQGHSFPFTFGQGTKLEIK

[0132] In a specific embodiment, the IL-23p19 antibody is an IgG1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain comprises the sequence of SEQ ID NO: 10 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

[0133] Array (array number: 9) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYLMHWVRQAPGQGLEWMGYINPYNEGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARNWDLPYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0134] Array (SEQ ID NO: 10) DIQMTQSPSSLSASVGDRVTITCRASQSISDYLHWYQQKPGKAPKLLIKYASQSMSGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQGHSFPFTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0135] Preferably, the IL-23p19 antibody is anti-IL-23p19 antibody 17D1-YTE disclosed in PCT application number PCT / CN2019 / 121261 (International filing date: November 27, 2019), which consists of the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0136] In some specific embodiments, the anti-IL-23p19 antibody is recombinantly expressed in HEK293 cells or CHO cells.

[0137] In some specific embodiments, IL-23p19 antibody formulations can be prepared according to the formulations containing anti-IL-23p19 antibody, methods for producing the same, and uses disclosed in PCT application number PCT / CN2021 / 093219 (International filing date: May 12, 2021).

[0138] In some specific embodiments of the present invention, the method comprises administering an anti-IL-23p19 antibody to subjects who have previously been treated with a biological agent for psoriasis vulgaris, wherein the anti-IL-23p19 antibody is administered to subjects who did not respond or responded poorly to the biological agent at weeks 0, 4, and 8, respectively, and thereafter once every 12 weeks.

[0139] Here, the dosage for each administration is 100 mg to 1000 mg. For example, the dosage for each administration is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. Preferably, the dosage for each administration is 200 mg.

[0140] Of these, poor response was defined as an sPGA score of 2 points or more, or a cumulative lesion area of ​​3% or more of skin lesions, or a failure of PASI to improve by 75% after the use of biological agents.

[0141] In some specific embodiments of the present invention, the method includes administering an anti-IL-23p19 antibody to subjects who have previously been treated with a biological agent for psoriasis vulgaris, and administering the anti-IL-23p19 antibody to subjects who respond to biological treatment at week 0 and every 12 weeks thereafter.

[0142] Here, the dosage for each administration is 100 mg to 1000 mg. Specifically, the dosage for each administration is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. Preferably, the dosage for each administration is 200 mg.

[0143] A response is defined as follows: after use of a biological agent, the sPGA score is 0 or 1, and the cumulative invasive surface area of ​​skin lesions is less than 3%, or the PASI improvement is 75% or greater.

[0144] In some specific embodiments of the present invention, the route of administration is subcutaneous injection.

[0145] In some specific embodiments of the present invention, the biological agent comprises a tumor necrosis factor α inhibitor / antagonist and / or an IL-17A inhibitor / antagonist. TNF-α inhibitors / antagonists include etanercept, infliximab, adalimumab, golimumab, and certolizumab. IL-17A inhibitors / antagonists include secukinumab and ixekizumab.

[0146] Furthermore, TNF-α inhibitors / antagonists include, but are not limited to, etanercept, infliximab, and adalimumab. IL-17A inhibitors / antagonists include, but are not limited to, secukinumab.

[0147] For example, previous treatment with biological agents: a. Patients receiving regular treatment at prescribed doses must meet the following conditions: - Use of IL-17 inhibitors for at least 4 months: Secukinumab is administered subcutaneously at a dose of 300 mg in weeks 0, 1, 2, 3, and 4, and thereafter every 4 weeks; ixekizumab is administered subcutaneously at a dose of 160 mg in week 0, and then at weeks 2, 4, 6, 8, 10, and 12, and thereafter every 4 weeks at a dose of 80 mg. - Use of TNF inhibitors for at least 4 months: Adalimumab 80 mg subcutaneously in week 0, 40 mg subcutaneously in week 1, and every 2 weeks thereafter; etanercept 25 mg twice weekly for the first 3 months, and then 50 mg once weekly or 25 mg twice weekly thereafter; infliximab 5 mg / kg intravenously in weeks 0, 2, and 6, and the same amount every 8 weeks thereafter.

[0148] or b. Patients who are not receiving regular treatment according to the prescribed dosage are defined as patients who have not met the previous dosage and administration interval, but for whom at least four months have passed since the last dose of the biological agent and the first dose of the biological agent.

[0149] Single-dose medication unit The effective amount of the anti-IL-23p19 antibody of the present invention is preferably a fixed dose selected from 100 mg to 1000 mg of anti-IL-23p19 antibody; preferably 50 mg to 800 mg, more preferably a fixed dose of 50 mg to 500 mg, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 2 A single-dose pharmaceutical unit containing 40 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, preferably 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, or 500 mg).

[0150] In some embodiments, a single drug dosage unit is a single drug dosage unit filled in a pre-filled auto-injector pen.

[0151] Medical kit A pharmaceutical kit comprising an effective amount of the anti-IL-23p19 antibody disclosed herein, which preferably comprises a fixed dose of 100 to 1000 mg, and more preferably 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of the anti-IL-23p19 antibody. Specifically, this also includes a package insert printed with instructions for the use of the anti-IL-23p19 antibody for the prevention or treatment of psoriasis vulgaris in a subject.

[0152] In some embodiments, the drug kit contains an anti-IL-23p19 antibody in the form of a single drug dose unit. In other embodiments, the single drug dose unit is filled into a pre-filled auto-injector pen.

[0153] Purpose Use of the anti-IL-23p19 antibody, single drug dose unit, or drug kit disclosed herein in the manufacture of a drug for the prevention or treatment of psoriasis vulgaris. [Examples]

[0154] Example 1. Preparation and purification of IL-23p19 antibody The antibody 17D1-YTE, which specifically binds to IL-23p19, was obtained as described in PCT application number PCT / CN2019 / 121261. This antibody has the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10. PCT application number PCT / CN2019 / 121261 is incorporated herein by reference in its entirety.

[0155] In short, this antibody is recombinantly expressed in CHO cells. The IL-23p19 antibody sample used in the present invention is purified by affinity chromatography, and the IL-23p19 antibody sample used in the formulation screening experiment of the present invention is purified by cation exchange chromatography.

[0156] Example 2. Clinical Trial Preclinical pharmacokinetic (PK), pharmacokinetic (PD), and toxicity studies demonstrated that the anti-IL-23P19 antibody has a clear target, a clear mechanism of action, and significant anti-inflammatory activity, and is predicted to reduce or eliminate skin lesions in subjects with psoriasis vulgaris, improve the severity of skin lesions, and decrease the cumulative body surface area of ​​skin lesions. The anti-IL-23P19 antibody exhibited linear PK characteristics in cynomolgus monkeys, had a long half-life, high bioavailability, high in vivo safety after short-term or long-term repeated administration to cynomolgus monkeys, and no risk of hemolysis or cytokine release in vitro.

[0157] A randomized, double-blind, placebo-controlled Phase I clinical trial was completed to investigate the safety and tolerability of a single dose escalation of the anti-IL-23p19 antibody of the present invention in healthy subjects. The results indicate that the anti-IL-23p19 antibody is safe and well-tolerated in healthy subjects.

[0158] The anti-IL-23p19 antibody of the present invention has completed a dose-finding, phase II, multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with moderate to severe plaque psoriasis, achieving its primary efficacy endpoint. The results of the phase II trial demonstrated that the anti-IL-23p19 monoclonal antibody significantly improved skin lesions in patients with moderate to severe plaque psoriasis and exhibited favorable overall safety and tolerability.

[0159] The results of the two trials described above demonstrated significant efficacy and safety of the anti-IL-23P19 antibody in Chinese subjects with moderate to severe psoriasis vulgaris, and that the benefits outweighed the risks. These data indicate the continuation of clinical trials for this product.

[0160] This study is a multicenter, open-label trial of an anti-IL-23p19 monoclonal antibody to evaluate the efficacy of switching subjects with psoriasis vulgaris who have previously been treated with biological agents to the anti-IL-23p19 monoclonal antibody of the present invention.

[0161] 3.1 Test Objectives ·Main purpose: To evaluate the effectiveness of switching subjects who have previously been treated with biological agents for psoriasis vulgaris to the anti-IL-23p19 antibody therapy of the present invention.

[0162] Secondary purposes: - To evaluate the safety of switching subjects with psoriasis vulgaris who have previously been treated with biological agents to anti-IL-23P19 antibody therapy. - To evaluate the impact on health-related quality of life of switching to anti-IL-23P19 antibody therapy in subjects with psoriasis vulgaris who have previously been treated with biological agents. - To evaluate the immunogenicity of switching to anti-IL-23P19 antibody therapy in subjects with psoriasis vulgaris who have previously been treated with biological agents.

[0163] 3.2 Test Evaluation Items • Primary efficacy endpoints The percentage of subjects whose physician-administered Static Overall Assessment (sPGA) score was zero (0 points) or nearly zero (1 point) and whose BSA was less than 3% at week 16.

[0164] • Secondary efficacy endpoints - The percentage of subjects whose physician-administered Static Overall Assessment (sPGA) score was zero (0 points) at week 16. - Percentage of subjects with a Dermatological Quality of Life Index (DLQI) score of 0 / 1 at week 16. - Percentage of subjects with an sPGA score of 0 or 1, an sPGA score of 0, and a DLQI score of 0 or 1 at week 44. - The percentage of subjects who maintained the sPGA score of 0 or 1, or sPGA score of 0 and DLQI score of 0 or 1 at week 16, at week 44.

[0165] • Other effectiveness evaluation items - Change in DLQI from baseline - Changes in psoriasis area and severity index (PASI) from baseline - Change in cumulative BSA of skin lesions from baseline - Percentage of subjects with BSA of 1% or less and 3% or less - Percentage of subjects with a PASI of 1 or less and 3 or less (only subjects with poor response at baseline) - Time to sPGA0 or 1 (only for subjects with poor response at baseline) - Time to sPGA0 (only for subjects with poor response at baseline)

[0166] • Safety evaluation items All adverse events, including serious adverse events. Changes in vital signs, physical examinations, clinical tests, electrocardiogram results, etc., before and after drug administration.

[0167] • Immunogenicity assessment The emergence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs).

[0168] 3.3 Test Plan This study is a multicenter, open-label trial primarily evaluating the efficacy of switching subjects receiving treatment with biological agents for psoriasis vulgaris to the anti-IL-23p19 antibody of the present invention.

[0169] The target population consists of male or female subjects aged 18 to 75 years with psoriasis vulgaris who, prior to screening, have used biological agents, including IL-17 inhibitors and tumor necrosis factor α (TNF-α) inhibitors, for the treatment of psoriasis vulgaris. Prior to screening, subjects may be either those who have been receiving regular treatment at prescribed doses (for at least 4 months) or those who have not been receiving regular treatment at prescribed doses (with at least 4 months between the last dose and the first dose of the biological agent).

[0170] Approximately 160 subjects are planned to be enrolled, and the proportion of subjects with poor response at baseline must be at least 30% of the total enrolled subjects. Subjects with poor response at baseline (sPGA of 2 points or more, or cumulative body surface area of ​​skin lesions of 3% or more, or PASI improvement rate of less than 75% after use of biological agents) will be switched to the anti-IL-23p19 antibody of the present invention. Subjects will receive 200 mg of the anti-IL-23p19 antibody by subcutaneous injection at weeks 0, 4, and 8, and then once every 12 weeks thereafter, until the final dose at week 32. Responders (sPGA of 0 or 1 point, and cumulative body surface area of ​​skin lesions of less than 3%, or PASI improvement rate of 75% or more after use of biological agents) will also be switched to the anti-IL-23p19 antibody of the present invention. Subjects will receive their first dose at week 0, and then once every 12 weeks thereafter, until the final dose at week 36. The switch to anti-IL-23p19 antibody therapy should be initiated within one week before or after the scheduled administration date of the biological agent. The screening period for this study should not exceed four weeks. Eligible subjects will be switched to the anti-IL-23p19 antibody therapy of the present invention, and follow-up will be completed at 44 weeks after the final dose.

[0171] 3.4 Selection Criteria Eligible subjects must meet all of the following selection criteria.

[0172] (1) Male or female between the ages of 18 and 75.

[0173] (2) The principal investigator determined that the subject was appropriate to continue treatment for psoriasis vulgaris with a biological agent.

[0174] (3) Previous treatment with biological agents a. Subjects receiving regular treatment according to the prescribed dosage must meet the following conditions: - Use of IL-17 inhibitors for at least 4 months: secukinumab 300 mg subcutaneously at weeks 0, 1, 2, 3, and 4, and thereafter every 4 weeks; ixekizumab 160 mg subcutaneously at week 0, and then at weeks 2, 4, 6, 8, 10, and 12, and thereafter every 4 weeks at 80 mg; - Use of TNF inhibitors for at least 4 months: Adalimumab 80 mg subcutaneously in week 0, 40 mg subcutaneously in week 1 and every 2 weeks thereafter; etanercept 25 mg twice weekly for the first 3 months, and then 50 mg once weekly or 25 mg twice weekly for the next 3 months; infliximab 5 mg / kg intravenously in weeks 0, 2, and 6, and the same amount every 8 weeks thereafter; or b. Subjects who are not receiving treatment regularly according to the prescribed dosage are defined as subjects who have not met the previous dosage and administration interval, but whose last dose of the biological agent was at least four months after the first dose of the biological agent.

[0175] (4) Subjects who respond to or do not respond to biological therapy at screening and baseline: a. A response is defined as follows: after use of a biological agent, the sPGA score is 0 or 1, and the cumulative BSA of skin lesions is less than 3%; or PASI improvement is 75% or greater; b. Poor response is defined as follows: failure to achieve an sPGA score of 2 points or more, a cumulative BSA of 3% or more in skin lesions, or a 75% improvement in PASI after use of a biological agent;

[0176] (5) A full understanding of the purpose of the study, a basic understanding of the pharmacological effects and possible side effects of the investigational drug; voluntarily signing informed consent in accordance with the spirit of the Declaration of Helsinki.

[0177] 3.5 Exclusion criteria The eligible subjects did not meet any of the following exclusion criteria: (1) Previous or current diagnosis of pustular psoriasis, erythrodermic psoriasis, or drug-induced psoriasis (e.g., psoriasis caused by beta-blockers, calcium channel inhibitors, etc.); or guttate psoriasis at the time of screening or prior to the first dose;

[0178] (2) Subjects who have previously used anti-IL-23p19 antibodies and IL-23 preparations;

[0179] (3) Subjects who received two different biological agents for the treatment of psoriasis within four months prior to screening;

[0180] (4) Subjects who have received topical treatment for psoriasis within two weeks prior to the first dose, or subjects who have received systemic treatment with non-biological agents or phototherapy within four weeks prior to the first dose;

[0181] (5) Use of natalizumab, B-cell or T-cell modulator (e.g., rituximab, abatacept, or bicilizumab) within 12 months prior to the first dose;

[0182] (6) No intention to avoid continuous sun exposure and other sources of ultraviolet radiation during the test period;

[0183] (7) The patient has received treatment with an experimental biological agent within 6 months prior to the first dose of the study drug, or has received experimental treatment within 30 days, or has been administered the study drug within 5 times its half-life, or has participated in a clinical trial;

[0184] (8) There is evidence that the subject has a severe, progressive, or uncontrolled cardiovascular, neuromuscular, hematological, respiratory, hepatic, or gastrointestinal, urinary, neurological, or psychiatric disorder;

[0185] (9) Opportunistic infections within 6 months prior to screening [e.g., herpes zoster (severe or recurrent), active cytomegalovirus infection, Pneumocystis jirovecii infection, histoplasmosis, aspergillosis, mycobacteriosis, etc.];

[0186] (10) A history of recurrent or chronic infection, including, but not limited to, chronic kidney infection, chronic chest infection (e.g., bronchiectasis), recurrent urinary tract infection, open wounds, drainage wounds, or skin infection wounds;

[0187] (11) A history of serious infection (e.g., sepsis, pneumonia, pyelonephritis), or a history of hospitalization for infection within two months prior to screening;

[0188] (12) Malignant tumor or history of malignant tumor (excluding squamous cell carcinoma of the skin, basal cell carcinoma, or focal cervical intraepithelial neoplasia that has been successfully excised and shows no signs of recurrence or metastasis within 5 years);

[0189] (13) Having or having had a lymphoproliferative disorder, or having had symptoms or signs suggestive of a lymphoproliferative disorder (e.g., lymphadenopathy and / or splenomegaly) within five years prior to screening;

[0190] (14) Tuberculosis status of subjects with a history of active tuberculosis, or suspected tuberculosis based on clinical symptoms or imaging findings of tuberculosis (including, but not limited to, pulmonary tuberculosis, lymphatic tuberculosis, tuberculous pleurisy, etc.), or who underwent an interferon-gamma release assay (IGRA) during the screening period. For subjects without symptoms of active tuberculosis and no findings of tuberculosis on imaging: • If the IGRA test result is negative, the subject meets the eligibility criteria; If the IGRA test result is inconclusive, a retest may be performed. If the retest result is also inconclusive, the subject does not meet the eligibility criteria. If the IGRA test result is positive, the subject may undergo screening and evaluation again after receiving prophylactic anti-tuberculosis treatment for at least one month. If the patient does not show symptoms of tuberculosis, tolerates anti-tuberculosis drugs well, and is willing to receive complete prophylactic anti-tuberculosis treatment during the study period, the patient may be enrolled based on the principal investigator's assessment; Subjects who have a positive IGRA test result prior to the initiation of biological therapy, have received complete prophylactic anti-tuberculosis treatment, and do not exhibit symptoms of active tuberculosis or tuberculosis findings on X-ray are eligible for enrollment;

[0191] (15) The person has received the Bacillus Calmette-Guérin (BCG) vaccine within 12 months prior to the first use of the study drug, or is scheduled to receive the BCG vaccine during the study period or within 12 months after the last study treatment;

[0192] (16) Having received a live vaccine or bacterial vaccine within three months prior to the first dose of the study drug, or being scheduled to receive a live vaccine or bacterial vaccine during the study period or within three months after the last treatment with the study drug;

[0193] (17) The results of hematological and blood biochemical tests during the screening period and baseline period meet the following conditions: • One of the following parameters—hemoglobin, red blood cells, white blood cells, neutrophils, or platelets—is below the lower limit of normal (LLN), and the abnormal value is deemed clinically significant by the principal investigator; • One of the following parameters—alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), or direct bilirubin (DBIL)—is greater than twice the upper limit of normal (ULN); • Creatinine (Cr) levels exceed ULN; patients who meet the requirements of the clinical trial protocol after re-examination can also be enrolled.

[0194] (18) The virus test result at the time of screening meets one of the following criteria: • Tested positive for human immunodeficiency virus (HIV) antibodies; • The patient is positive for hepatitis C virus (HCV) antibodies and has no history of successful treatment. Successful treatment is defined as being HCVRNA negative at least 24 weeks after the start of antiviral drug therapy. Hepatitis B virus (HBV) screening includes testing for at least hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (HBcAb), if HBsAg is positive; or if HBsAg is negative and only HBcAb is positive, then HBV DNA is tested, and the result is positive: • Positive for syphilis-specific antibodies (excluding subjects whose non-syphilis antibody titers became negative after standard syphilis treatment);

[0195] (19) Clinically significant 12-lead electrocardiogram (ECG) abnormalities at screening: QTcF > 450 ms, shortened or delayed PR interval, second- or third-degree atrioventricular block, premature excitation syndrome, prolonged QT syndrome, or severe arrhythmias requiring treatment;

[0196] (20) Previous severe drug or food allergies, and / or allergies to diagnostic reagents or their components;

[0197] (21) A history of alcohol and / or drug abuse within 12 months prior to screening;

[0198] (22) Pregnant or breastfeeding women, or women of childbearing age who have tested positive for pregnancy at the time of screening and before administration;

[0199] (23) Subjects who are planning to give birth during the study period or within 6 months after administration of the study drug, or subjects who do not intend to take any contraceptive measures (such as condoms) that the physician deems appropriate during the study period;

[0200] (24) A subject whom the researcher has determined to be ineligible to participate in this clinical trial for any reason.

[0201] 3.6 Test drug, dosage, and method of administration Poor response patients: Subcutaneously inject 200 mg of the anti-IL-23p19 antibody of the present invention at weeks 0, 4, 8, 20, and 32; Respondents: Subcutaneously inject 200 mg of the anti-IL-23p19 antibody of the present invention at weeks 0, 12, 24, and 36; Dosage form of the test drug: Injectable. Specification is 100 mg (1 mL) / 1 vial. The formulation is as follows: 100.0 mg / mL recombinant anti-interleukin 23p19 subunit antibody, 0.76 mg / mL histidine, 1.08 mg / mL histidine hydrochloride, 50.00 mg / mL sorbitol, 80 mg / mL polysorbate (pH 6.0).

[0202] The following treatments were prohibited during the treatment period. • Drugs and treatments prohibited before the first dose will remain prohibited during the study period, in accordance with the relevant exclusion criteria. Prohibited drugs / treatments during the study period are listed in the table below:

[0203] [Table 3]

[0204] If a subject is using a prohibited drug that has been evaluated as having a significant impact on efficacy and safety (for example, a biological agent, a strong or extremely strong topical therapy lasting more than one week, or a non-biological systemic drug), treatment must be discontinued.

[0205] During administration, the administration of hepatotoxic drugs must be avoided.

[0206] 3.7 Treatment Compliance Participants received the study treatment at the clinical trial site, and treatment compliance was monitored using medication records, participant medical records, and eCRFs.

[0207] 3.8 Indicators related to effectiveness evaluation A. Psoriasis Area and Severity Index (PASI) To the greatest extent possible, the physician who performed the PASI assessment on the subject during the screening / baseline phase should also perform the PASI assessment on the subject during subsequent follow-up examinations. PASI90 is defined as an improvement of 90% or more in the PASI score from baseline. PASI75 is defined as an improvement of 75% or more in the PASI score from baseline. PASI100 is defined as a 100% improvement in the PASI score from baseline.

[0208] B. Static overall assessment by physician (sPGA) sPGA records a physician's assessment of the subject's psoriasis condition, including the following evaluation items: induration, scaling, and erythema. Wherever possible, the physician who performed the sPGA assessment at screening / baseline also performed the sPGA assessment on the subjects at subsequent visits.

[0209] C. Quality of Life Index (DLQI) in Dermatology During visits that included DLQI assessment, the DLQI assessment was performed before all other visit activities (such as examinations, procedures, psoriasis assessment, adverse event and concomitant medication collection) throughout the study period.

[0210] D. Photographs of skin lesions To obtain more efficacy evaluation data, photographs of the subjects' skin condition (excluding the perineum) will be taken each time an efficacy evaluation is performed.

[0211] 3.9 Safety Evaluation I. Clinical Laboratory Tests Safety assessments using routine clinical tests include the clinical tests listed in the table below. [Table 4] HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e antibody; HBeAg, Hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antibody Original; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV, Human Immunodeficiency Virus Failure virus.

[0212] The relevant clinical tests will be performed under fasting conditions.

[0213] II. Clinical Laboratory Tests Clinical examinations include general physical examinations, vital signs (including body temperature, pulse, and blood pressure), 12-lead electrocardiogram (12-lead ECG), chest X-ray, severe allergic reactions, injection site reactions, cardiovascular events (including major cardiovascular events (e.g., cardiovascular-related death, cerebrovascular-related death, non-fatal myocardial infarction, and non-fatal stroke) and other cardiovascular events known in the art), and psychiatric-related events.

[0214] 3.10 Immunogenicity Approximately 5 mL of whole blood was collected, the serum was separated and aliquoted, and then frozen for ADA and NAb analysis.

[0215] 3.11 Statistical analysis method A. General statistical analysis methods In this study, efficacy and safety data will be summarized separately depending on whether the subjects have previously responded to biological agents.

[0216] No group comparisons were performed in this study. Measurement data are described using the number of subjects, mean, standard deviation, median, Q1, Q3, minimum, and maximum values. Count data are described using frequency and percentage. All statistical analyses were performed using SAS v9.4 (or later).

[0217] B. Baseline characteristics of the subjects The demographic or baseline characteristics of the subjects, as well as diagnostic and treatment information for the study disease, medical history, and previous concomitant therapies, will be described and statistically analyzed.

[0218] C. Analysis of effectiveness The evaluation of efficacy indicators is summarized based on the presence or absence of a response, using a safety analysis set.

[0219] 1) Analysis of primary efficacy endpoints The primary efficacy endpoint in this study was the percentage of subjects who achieved an sPGA score of 0 (clean) or 1 (nearly clean) at week 16. Subjects with no sPGA score at week 16, or subjects who received other psoriasis treatments prior to week 16 that could affect efficacy assessment, were considered ineligible for sPGA at week 16. The number and percentage of subjects who achieved sPGA0 / 1 were calculated, and the 95% confidence interval (CI) was calculated using the Clopper-Pearson method.

[0220] 2) Analysis of secondary efficacy endpoints Binary Variable Analysis Secondary efficacy endpoints for binary variables include the proportion of subjects with an sPGA score of 0 and a DLQI score of 0 / 1 at week 16; the proportion of subjects with an sPGA score of 0 / 1, an sPGA score of 0, and a DLQI score of 0 / 1 at week 44; the proportion of subjects who maintained the same scores at week 44 among those with an sPGA score of 0 / 1, an sPGA score of 0, and a DLQI score of 0 / 1 at week 16; the proportion of subjects with a BSA of ≤1% and ≤3%; and the proportion of subjects with a PASI of ≤1 and ≤3 (only subjects with poor response at baseline).

[0221] The analysis method was the same as that for the primary efficacy endpoint. Analysis of continuous variables Secondary efficacy endpoints for continuous variables included the change from baseline in DLQI, PASI, and cumulative skin lesion area (BSA) at each visit.

[0222] Descriptive statistics for each continuous efficacy endpoint (number of cases, mean, standard deviation, median, Q1, Q3, minimum, maximum, etc.) are summarized for each visit. The 95% confidence interval (CI) for the mean is also calculated. Furthermore, a graph showing the change in the mean over time is created.

[0223] Analysis of time variables leading up to the event (only for subjects who showed poor response at baseline) Secondary efficacy endpoints for the time-to-event variable include the sPGA score 0 / 1 and the time to reach an sPGA score of 0, which is defined as the time from the first dose of the investigational drug until an sPGA score of 0 / 1 or 0 is achieved. If a subject does not reach the corresponding sPGA score at the end of the study, the data is censored at the subject's last efficacy assessment.

[0224] The number and percentage of subjects who reached the corresponding sPGA score and those for whom censored data were compiled. The median and its 95% confidence interval (CI) were calculated using the Kaplan-Meier method, and a KM curve was plotted.

[0225] D. Safety analysis Safety analysis is based on a safety analysis set.

[0226] 1) Drug exposure This involves summarizing the subjects' exposure to the investigational drug, the duration of drug use, and compliance during the trial period.

[0227] 2) Adverse events Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects with various categories of AEs (treatment-related adverse events, drug-related adverse events, AESIs, SAEs, etc.) were summarized, and the occurrence of various AEs was further summarized using the MedDRA organ-specific major classifications and preferred terminology. The association and severity of each AE with the investigational drug were also analyzed.

[0228] 3) Clinical Tests For routine blood tests, blood biochemistry tests, and other indicators, the measured values ​​and changes from baseline at each time point are described using the number of cases, mean, standard deviation, median, Q1, Q3, and minimum and maximum values ​​per visit. A cross-classification table is used to describe changes in normal and abnormal states before and after drug administration. For urine tests, a cross-classification table will be used to describe the changes in normal and abnormal conditions before and after treatment.

[0229] 4) 12-lead electrocardiogram Quantitative electrocardiogram (ECG) indicators and their changes from baseline will be summarized using descriptive statistics. Changes in normal and abnormal states before and after treatment will be summarized using a cross-classification table.

[0230] 5) Vital signs, physical examination, and other safety-related tests Vital sign measurements and their changes from baseline are summarized using descriptive statistics. List subjects who showed abnormal changes from baseline in physical examinations and other safety tests.

[0231] E. Immunogenicity Throughout the entire study period, the positive rates of anti-IL-23p19 antibodies (ADA) and neutralizing antibodies (NAb) will be summarized using descriptive statistics.

[0232] 3.12 Results The above demonstrates that switching patients with psoriasis vulgaris who have previously received treatment with biological agents to the anti-IL-23p19 antibody therapy of the present invention exhibits excellent efficacy and safety.

[0233] • Anti-IL-23P19 antibodies demonstrated good safety: In single-dose studies in healthy subjects and repeated-dose studies in psoriasis patient populations, overall safety was good, the incidence of adverse events was not significantly increased compared to the placebo group, and no dose-dependent safety events were observed.

[0234] • Increasing the loading dose exposure (average concentration) can improve the PASI90 achievement rate at week 16: within 16 weeks, the average concentration of anti-IL-23P19 antibody (C avg,16w Increasing the dosage of anti-IL-23P19 antibody can improve the rate of achieving PASI90 at week 16 in the psoriasis patient population. Simulation results from a robust PopPK / PASI model showed that after subcutaneous injection of 200 mg of anti-IL-23P19 antibody at weeks 0, 4, and 8, approximately 57.5% of the psoriasis patient population achieved PASI90 at week 16.

[0235] • Long-term interval (Q12W) maintenance dosing can maintain long-term benefits in the psoriasis patient population: Simulation results from a robust PopPK / PASI model showed that a 200 mg Q12W maintenance dosing regimen was used, resulting in an approximately 88% long-term (52-week) PASI90 achievement rate. Long-term maintenance dosing regimens are expected to be the simplest and most effective treatment plan for psoriasis patients.

[0236] The efficacy of switching patients with psoriasis vulgaris who have previously received interleukin-17 antagonists or antitumor necrosis factor antagonists to the anti-IL-23p19 antibody treatment of the present invention. Subjects who showed a clinical response at baseline received 200 mg of anti-IL-23p19 antibody subcutaneously once every 12 weeks. Subjects who showed a poor clinical response at baseline received 200 mg of anti-IL-23p19 antibody subcutaneously every 0 weeks, every 4 weeks, every 8 weeks, and then every 12 weeks thereafter. The results are shown in the table below. [Table 5]

[0237] The test data showed that after the subjects who had a clinical response at baseline were switched to the anti-IL-23P19 antibody of the present invention, 85.3% of the subjects maintained a clinical response even at week 16 (the cumulative body surface area of skin lesions was less than 3%, and the static global assessment score sPGA by the physician was 0 or 1), and approximately 85% was maintained during the observation from week 16 to week 36; after the subjects who did not have a clinical response at baseline were switched to the anti-IL-23P19 antibody, the proportion of subjects who achieved a response gradually increased, and the proportion of subjects who achieved a response increased to 52.1% at week 16, and the same proportion of subjects maintained the response thereafter.

[0238] It can be seen that the anti-IL-23p19 antibody of the present invention can effectively treat subjects who were previously administered an interleukin 17 antagonist or an anti-tumor necrosis factor antagonist for the treatment of psoriasis vulgaris.

[0239] Although the exemplary embodiments of the present invention have been described above, those skilled in the art should understand that these disclosures are merely illustrative, and various other substitutions, applications, and modifications are possible within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments described herein.

Claims

1. A method for treating psoriasis vulgaris in a subject, comprising administering an effective amount of anti-IL-23p19 antibody to the subject, wherein The method involves an anti-IL-23p19 antibody comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 in the heavy chain variable region comprises SEQ ID NO: 1, the amino acid sequence of CDR2 in the heavy chain variable region comprises SEQ ID NO: 2, and the amino acid sequence of CDR3 in the heavy chain variable region comprises SEQ ID NO: 3; the amino acid sequence of CDR1 in the light chain variable region comprises SEQ ID NO: 4, the amino acid sequence of CDR2 in the light chain variable region comprises SEQ ID NO: 5, and the amino acid sequence of CDR3 in the light chain variable region comprises SEQ ID NO:

6.

2. The method according to claim 1, wherein the anti-IL-23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence having at least 90%, 95%, 98%, or 99% identity thereto.

3. A method according to claim 1 or 2, wherein the anti-IL-23p19 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the sequence described in SEQ ID NO: 9 or a sequence having at least 90% identity with SEQ ID NO: 9, and the light chain comprises the sequence described in SEQ ID NO: 10 or a sequence having at least 90% identity with SEQ ID NO:

10.

4. The method according to any one of claims 1 to 3, wherein the subject has been treated with a biological agent for psoriasis vulgaris prior to treatment.

5. The method according to any one of claims 1 to 4, wherein the subject has been regularly administered a prescribed dose of a biological agent (for example, for at least four months).

6. The method according to any one of claims 1 to 4, wherein the subject has never been regularly administered a prescribed dose of the biological agent (for example, for at least four months between the last dose of the biological agent and the first dose).

7. The method according to any one of claims 1 to 6, wherein the subject had not responded to or had a poor response to previous biological therapy.

8. The method according to claim 7, wherein, after use of the biological agent, the subject's sPGA score is 2 or higher, or the cumulative body surface area of ​​skin lesions is 3% or higher, or a 75% improvement in PASI has not been achieved.

9. The method according to any one of claims 1 to 8, wherein the anti-IL-23p19 antibody is administered in a two-stage dosing regimen including a treatment phase and a maintenance phase to subjects who have not responded or have had a poor response to previous biological therapy.

10. The method according to claim 9, wherein during the treatment period, the anti-IL-23p19 antibody is administered at a frequency of once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or once every twelve weeks.

11. The method according to claim 9 or 10, wherein the treatment period includes administering the anti-IL-23p19 antibody at week 0, week 4, and week 8.

12. The method according to any one of claims 9 to 11, wherein during the maintenance period, the anti-IL-23p19 antibody is administered at a frequency of once every 4 weeks, once every 8 weeks, once every 12 weeks, once every 16 weeks, once every 20 weeks, or more, for a period of at least 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or longer.

13. The method according to any one of claims 9 to 12, wherein during the maintenance period, the anti-IL-23p19 antibody is administered once every 12 weeks until the final dose at week 32.

14. A method according to any one of claims 1 to 13, wherein the anti-IL-23p19 antibody is administered to a subject who has not responded or has responded poorly to a prior biological therapy, at week 0, week 4, and week 8, and thereafter at once every 12 weeks, for example, the anti-IL-23p19 antibody is administered at week 0, week 4, and week 8, and thereafter at once every 12 weeks until the final dose at week 32; or, as an alternative example, the anti-IL-23p19 antibody is administered at 200 mg at week 0, week 4, and week 8, and thereafter at once every 12 weeks until the final dose at week 32.

15. The method according to any one of claims 1 to 6, wherein the subject has responded to prior treatment with a biological agent, or the subject is being treated with a biological agent and is still responding.

16. The method according to claim 15, wherein, after use of the biological agent, the subject's sPGA score is 0 or 1, and the cumulative body surface area of ​​skin lesions is less than 3%, or an improvement of 75% or more in PASI is achieved.

17. The method according to any one of claims 15 to 16, wherein the anti-IL-23p19 antibody is administered in week 0.

18. The method according to any one of claims 15 to 17, wherein the anti-IL-23p19 antibody is administered at a frequency of once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or more.

19. The method according to any one of claims 15 to 18, wherein the anti-IL-23p19 antibody is administered in week 0, and thereafter administered once every 12 weeks.

20. The method according to any one of claims 15 to 19, wherein the anti-IL-23p19 antibody is administered to a subject who has responded to a prior biological therapy in week 0, and thereafter administered once every 12 weeks for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer.

21. A method according to any one of claims 1 to 20, wherein the dose of the anti-IL-23p19 antibody administered each time is 100 mg to 1000 mg, preferably 150 mg to 800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, preferably 200 mg / dose.

22. The method according to any one of claims 1 to 21, wherein the biological agent comprises a tumor necrosis factor α inhibitor / antagonist and / or an IL-17A inhibitor / antagonist.

23. The method according to claim 22, wherein the TNF-α inhibitor / antagonist includes etanercept, infliximab, adalimumab, golimumab, and trastuzumab.

24. The method according to claim 22, wherein the IL-17A inhibitor / antagonist comprises secukinumab and ixekizumab.

25. The method according to any one of claims 1 to 24, wherein the anti-IL-23p19 antibody is formulated into a liquid pharmaceutical composition for administration.

26. The method according to claim 25, wherein the liquid pharmaceutical composition is an injectable preparation.

27. The method according to any one of claims 1 to 26, wherein the anti-IL-23p19 antibody or pharmaceutical composition is administered by subcutaneous injection.

28. Use of the anti-IL-23p19 antibody or a pharmaceutical composition comprising the anti-IL-23p19 antibody in the preparation of a pharmaceutical for the treatment of psoriasis vulgaris in a subject who has previously been treated with a biological agent for psoriasis vulgaris, wherein the anti-IL-23p19 antibody is as described in any one of claims 1 to 3.

29. The use according to claim 28, wherein the subject is one of the subjects described in any one of claims 4 to 8 and claims 15 to 16.

30. A single drug administration unit comprising the anti-IL-23p19 antibody according to any one of claims 1 to 3.

31. The single drug dosage unit according to claim 30, wherein the single drug dosage unit contains the following dosages of the anti-IL-23p19 antibody: a fixed dose of 10 to 1000 mg, preferably a fixed dose of 50 to 800 mg, more preferably 50 to 500 mg, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 23 Fixed doses of 0 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, preferably fixed doses of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, or 500 mg.

32. The single drug administration unit according to claim 30 or 31, wherein the single drug administration unit is a single drug administration unit filled in a pre-filled auto-injector pen.

33. A pharmaceutical kit comprising a single drug administration unit according to any one of claims 30 to 32, and optionally a package insert containing instructions for the use of the anti-IL-23p19 antibody in the prevention or treatment of psoriasis vulgaris in a patient.

34. Use of a single drug administration unit according to any one of claims 30 to 32 or a drug kit according to claim 33 in the manufacture of a drug for the treatment of psoriasis vulgaris.

35. A single drug administration unit according to any one of claims 30 to 32 or a drug kit according to claim 33 for use in the treatment of psoriasis vulgaris.

36. A single drug dose unit or drug kit for use in a subject according to any one of claims 4 to 8 and claims 15 to 16, for use according to claim 34 or claim 35.

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